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dc.contributor.authorMirantes Barbeito, Cristina
dc.contributor.authorEritja Sánchez, Núria
dc.contributor.authorDosil, Maria Alba
dc.contributor.authorSantacana Espasa, Maria
dc.contributor.authorPallares, Judit
dc.contributor.authorGatius Calderó, Sònia
dc.contributor.authorBergadà Bertran, Laura
dc.contributor.authorMaiques Carlos, Oscar
dc.contributor.authorMatias-Guiu, Xavier
dc.contributor.authorDolcet Roca, Xavier
dc.description.abstractPTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The role of PTEN in carcinogenesis has been validated by knockout mouse models. PTEN heterozygous mice develop neoplasms in multiple organs. Unfortunately, the embryonic lethality of biallelic excision of PTEN has inhibited the study of complete PTEN deletion in the development and progression of cancer. By crossing PTEN conditional knockout mice with transgenic mice expressing a tamoxifen-inducible Cre-ERT under the control of a chicken actin promoter, we have generated a tamoxifeninducible mouse model that allows temporal control of PTEN deletion. Interestingly, administration of a single dose of tamoxifen resulted in PTEN deletion mainly in epithelial cells, but not in stromal, mesenchymal or hematopoietic cells. Using the mT/mG double-fluorescent Cre reporter mice, we demonstrate that epithelial-specific PTEN excision was caused by differential Cre activity among tissues and cells types. Tamoxifen-induced deletion of PTEN resulted in extremely rapid and consistent formation of endometrial in situ adenocarcinoma, prostate intraepithelial neoplasia and thyroid hyperplasia. We also analyzed the role of PTEN ablation in other epithelial cells, such as the tubular cells of the kidney, hepatocytes, colonic epithelial cells or bronchiolar epithelium, but those tissues did not exhibit neoplastic growth. Finally, to validate this model as a tool to assay the efficacy of anti-tumor drugs in PTEN deficiency, we administered the mTOR inhibitor everolimus to mice with induced PTEN deletion. Everolimus dramatically reduced the progression of endometrial proliferations and significantly reduced thyroid hyperplasia. This model could be a valuable tool to study the cell-autonomous mechanisms involved in PTEN-loss-induced carcinogenesis and provides a good platform to study the effect of anti-neoplastic drugs on PTEN-negative tumors.ca_ES
dc.publisherCompany of Biologistsca_ES
dc.relation.isformatofReproducció del document publicat a
dc.relation.ispartofDisease Models & Mechanisms, 2013, vol. 6, p. 710-720ca_ES
dc.rightscc-by-nc-sa, (c) Company of Biologists, 2013ca_ES
dc.titleAn inducible knockout mouse to model the cellautonomous role of PTEN in initiating endometrial, prostate and thyroid neoplasiasca_ES

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cc-by-nc-sa, (c) Company of Biologists, 2013
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